Biomedical subjects

Asna A Siddiqui

Publications and source records attributed to Asna A Siddiqui.

3 recordsLinked to original sources

PubMed2006

Immune dysfunction in HIV-seronegative, Cryptococcus gattii meningitis.

The pathophysiology of meningitis caused by Cryptococcus gattii in apparently immunocompetent individuals remains unclear. We measured multiple cytokines in CSF from a HIV-seronegative, apparently immunocompetent, Thai patient with C. gattii meningitis, over the first 2 weeks of antifungal therapy. Levels of proinflammatory IFN-gamma, TNF-alpha, and IL-6 were very low compared to patients with HIV-related Cryptococcus neoformans meningitis and of IL-10 very high. While patients with C. gattii meningitis may be a heterogeneous group, these data suggest in this case a maladapted immune response to cryptococcal exposure had allowed progression to clinical cryptococcal disease.

Adult↗

PubMed2006

Role of capsule and interleukin-6 in long-term immune control of Cryptococcus neoformans infection by specifically activated human peripheral blood mononuclear cells.

Cryptococcus neoformans is a frequent cause of meningoencephalitis in immunosuppressed individuals. To better understand the mechanisms of a protective immune response to C. neoformans, a long-term in vitro model of human immune control of cryptococcal infection was developed. Peripheral blood mononuclear cells (PBMC) prestimulated with heat-killed C. neoformans significantly restricted the growth of C. neoformans after a subsequent live infection compared to that with unstimulated PBMC. Live infection with encapsulated C. neoformans was controlled for as long as 10 days, while infection with acapsular organisms could sometimes be eradicated. During immune control, fungal cells were both intracellular and extracellular within aggregates of mononuclear phagocytes and lymphocytes. Optimal immune control depended on the presence of both CD4+ and CD8+ T cells. Immune control of cryptococcal growth was more effective following prestimulation with acapsular compared with encapsulated organisms. Prestimulation with acapsular organisms was associated with a significant and prolonged increase in interleukin-6 (IL-6) production compared with prestimulation with encapsulated C. neoformans. Addition of IL-6 and depletion of CD25+ T cells prior to prestimulation and infection with encapsulated organisms resulted in reductions in cryptococcal growth that reached borderline statistical significance. Depletion of CD25+ T cells significantly reduced cryptococcal growth in wells with unstimulated PBMC. The results demonstrate an association between high levels of IL-6 and resistance to infection and, through suppression of IL-6 release, an additional mechanism whereby the cryptococcal capsule subverts a protective immune response. Further work is required to clarify the mechanism of action of IL-6 in this setting and any interaction with regulatory T cells.

Bacterial Capsules↗

PubMed2005

IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis.

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.

Cryptococcus neoformans↗